Cannabinoid (CB) components of marijuana are known to exert behavioral and psychotropic effects but also to possess therapeutic properties including analgesia, ocular hypotension, and antiemesis. CBs-based medications are now being used for treatment of a wide range of medical conditions, including neuropathic pain, pain related to cancer and trauma, spasticity associated with multiple sclerosis, fibromyalgia, and others. This invention generally relates to treatment and/or prevention of hyper and hypokinetic movement symptoms associated with cannabinoid-responsive diseases and disorders in subjects in need thereof, as well as the method of administering therapeutically-effective amount of a pharmaceutical compound containing CBs.
CBs are a group of chemicals known to activate CB receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids. Synthetic CBs are chemicals with similar structures to plant CBs or endocannabinoids. Plant cannabinoids can also be isolated such that they are “essentially pure” compounds. These isolated CBs are essentially free of the other naturally occurring compounds, such as, other minor CBs and molecules such as terpenes.
The methods and compounds of the proposed invention are intended for treatment of multiple diseases, disorders, and conditions such as: HD; Wilson's Disease; Sydenham's Chorea; Chorea Gravidarum; Autosomal Dominant Neurogenetic Syndrome; Huntington's Disease-Like Syndrome; Prion Disease; Spinocerebellar Ataxias; Neuroacanthocytosis; Dentatorubral-Pallidoluysian Atrophy; Brain Iron Accumulation Disorders; Friedreich's Ataxia; Mitochondrial Disease; Rett Syndrome; Cerebrovascular Disease; Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS); Levodopa-Induced Dyskinesia (LID), anti-convulsants and anti-psychotics drugs-related symptoms; Systemic Lupus Erythematosus; Antiphospholipid Syndrome; Tourette Syndrome (TS); Thyrotoxicosis; Polycythaemia Rubra Vera; Spongiform Encephalopathies; Coeliac Disease; PD; metabolic and endocrine-related diseases and disorders; athetosis-related to damage or degeneration of basal ganglia; minor tranquilizers and alcohol withdrawal syndromes; symptoms or side effects associated with anti-retroviral therapy, chemotherapy and radiation therapy.
Other diseases, disorders and conditions that cause athetosis, dystonia, tremors, tics, myoclonus, stereotypies, dyskinesia, restless legs syndrome, and Periodic Limb Movement Disorder (PLMD) are also contemplated by the invention. In addition, the methods of the invention may be used to alleviate, or relief symptoms or side effects associated with anti-retroviral therapy, chemotherapy, radiation therapy, and treatment of chemical withdrawal. Certain diseases and disorders are briefly outlined below, and the possible mechanisms of CB action are exemplified with treatment of certain diseases that cause hyperkinetic or hypokinetic movement symptoms.
Most hyperkinetic and hypokinetic movement disorders are caused by a dysfunction of basal ganglia-thalamo-cortical loops. Central CB receptors are located in large quantities in the output nuclei of the basal ganglia (globus pallidus, substantia nigra pars reticulata). It suggests that they could be involved in the regulation of motor activity. There is evidence that endogenous CB transmission plays a role in the manipulation of other transmitter systems within the basal ganglia by increasing GABAergic transmission, inhibiting glutamate release and affecting dopaminergic uptake.
In recent years a limited number of clinical trials in humans demonstrated that CBs might be useful in the treatment of movement disorders. It has been suggested that an endogenous CB tone participates in the control of movements and, therefore, the central Endo-Cannabinoid System (ECS) might play a role in the pathophysiology of these diseases. There is also limited evidence that CBs are of therapeutic value in the treatment of tics in TS, the reduction of LID in PD and some forms of tremor and dystonia. There is also evidence that CBs are useful in the treatment of chorea in HD and hypokinetic parkinsonian syndromes. Currently, treatments of these and similar diseases are focused on relieving symptoms and preventing complications because there is no curative therapy. Medical interventions include: physical therapy, immunosuppressive medication, hormone replacement therapy, blood transfusions (if blood is affected), anti-inflammatory medication, pain medication, and others.
Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of PD and HD. Clinical observations and clinical trials of CB-based therapies suggest a possible benefit of CBs for tics.
The primary CB receptor subtypes are CB receptors type 1 (CB1) and type 2 (CB2). CB1 receptors are highly expressed in the Central Nervous System (CNS), especially the basal ganglia, and also identified in almost all peripheral tissues and cell types. CB2 receptors are expressed primarily in the immune system, where they modulate inflammation, but are also expressed in the CNS, particularly in neurons within the dorsal vagal motor nucleus, the nucleus ambiguous, the spinal trigeminal nucleus, and microglia. CB2 receptors were also found in the basal ganglia and studies suggest that impairment of these receptors may be associated with dyskinesia. While most actions of CBs are related to CB1 and CB2 receptors, other receptor types have been described, including the Transient Receptor Potential Vanilloid type 1 (TRPV1) cation channel, the GTP-binding Protein-coupled Receptor GPR55, the abnormal-CBD receptor, and the Peroxisome-Proliferator-Activated Receptor (PPAR). (Kluger, Triolo, Jones, & Jankovic, 2015)
Endogenously produced CBs (eCBs) are lipophilic compounds that demonstrate varying degrees of affinity for G-protein coupled CB receptors and include anandamide and 2-arachidonoglycerol. eCBs primarily function through retrograde signaling, wherein post-synaptic activity leads to eCB production and release with backward transmission across the synapse to depress presynaptic neurotransmitter release. The ECS may also support synapse formation and neurogenesis. Within the basal ganglia, eCBs and CB1 receptors tend to increase GABAergic and inhibit glutamatergic transmission. eCBs also tend to inhibit dopamine release through GABAergic mechanisms. eCBs are not stored and are quickly degraded after exerting a transient and localized effect. Removal of eCBs from the extracellular space occurs through cellular uptake and metabolism with anandamide degraded primarily by Fatty Acid Amide Hydrolysis (FAAH) and 2-AG degraded by monoacylglycerol lipase. (Kluger, Triolo, Jones, & Jankovic, 2015)
According to Kluger, Triolo, Jones, and Jankovic, and as further suggested in the preclinical studies shown in FIG. 3, a number of PD and HD studies in animal models suggest that CB-based therapies may reduce neurodegeneration and reduce hyperkinetic activity. (Kluger, Triolo, Jones, & Jankovic, 2015) The U.S. Pat. No. 6,630,507 referenced herein, provides a list of CBs useful in certain neurodegenerative diseases such as PD, Alzheimer's Disease (AD), and dementia caused by human immunodeficiency virus. A number of recent studies conclude that CBs may offer neuroprotection through both receptor-mediated and receptor-independent mechanisms. According to Sagredo, et al., CBs are capable of reducing oxidative damage by acting as scavengers of Reactive Oxygen Species (ROS) and enhancing endogenous antioxidant defenses. (Sagredo, et al., 2007) Certain CBs, such as CBD and THC may appear to exhibit this property independent of CB1 and CB2 receptor modulation. These CBs also exhibit anti-inflammatory effects by inhibiting reactive microglia and cytokine release. There is also evidence that CB1 agonists reduce excitotoxicity by suppressing glutamatergic activity, subsequent calcium ion influx, and nitric oxide production. (Romero & Orgado, 2009)
Experimental animal models indicate that HD is associated with early and widespread reductions in the ECS, particularly CB1 receptors in the striatum. CB1 receptors mediate brain-derived neurotrophic factor expression and CB1 receptor loss is associated with exacerbation of symptoms, neuropathology, and molecular pathology in the striatum. Moreover, CBs-based therapies generally show neuroprotection in several animal models through both CB receptor mediated and independent effects. (Kluger, Triolo, Jones, & Jankovic, 2015) Therapeutic studies of CB-based agents in HD animal models suggest that CB1 and endovanilloid receptor agonists, and anandamide reuptake inhibitors are capable of alleviating hyperkinesia. This therapeutic potential is likely to be realized in early phases of HD because of progressive loss of CB1 receptors in advanced stages. (Lastres-Becker, et al., 2001)
Experimental models of PD show increased ECS activity in the basal ganglia, including increased CB1 mRNA levels, CB1 activity, anandamide levels, and decreased CB clearance. These changes appear to be associated with movement suppression and may be reversed by chronic levodopa treatment. Importantly, many CBs demonstrate neuroprotective effects in several models of PD. These effects appear to be mediated by both CB receptor dependent and independent mechanisms including antioxidant effects, reduced microglia activation, and modulation of glial-neuron interactions. (Kluger, Triolo, Jones, & Jankovic, 2015) Animal studies further suggest that CBs may improve motor symptoms of PD and LID. CB1 agonists inhibit basal ganglia dopamine release and are therefore could be ineffective in alleviating PD motor symptoms. Indeed, CB1 agonists have been shown to exacerbate bradykinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primates. (Meschler, Howlett, & Madras, 2001)
However, CB1 agonists have also been reported to improve motor impairments, possibly through nondopaminergic mechanisms including interactions with adenosine A2A receptors. Studies of CB1 antagonists are more consistent in improving motor symptoms without increasing dyskinesias. These effects appear to involve nondopaminergic mechanisms including enhanced striatal glutamate release and may be greater in animals with more severe striatonigral degeneration. (Kluger, Triolo, Jones, & Jankovic, 2015)
It is conceivable that CB1 agonists also reduce overactivity of the globus pallidus interna and improve dystonia by reducing GABA reuptake. In support of this idea, the CB1 and CB2 agonist WIN55,212-2 produces antidystonic effects in a mutant hamster model of dystonia, increases the antidystonic efficacy of benzodiazepines and is reversed by rimonabant, a selective CB1 antagonist. Animal models suggest that CBs may reduce Multiple Scleroses (MS)-related tremor, an effect that appears to be selectively mediated by CB1 receptors.
Case reports of smoked cannabis, oral THC, and case series of smoked cannabis suggest that CBs may be beneficial for tics in patients with TS. Similarly, a survey of 64 TS patients found that 17 (27%) had tried marijuana and 14 of them (82%) found it helpful for tics and behavioral disturbances. (Müller-Vahl, Kolbe, Schneider, & Emrich, 1998) There is also evidence suggesting that CBs may be effective for ataxia, myoclonus or restless legs syndrome. Two case reports suggest ataxia (in combination with spasticity) in MS may improve following smoked cannabis or oral THC. (Meinck, Schonle, & Conrad, 1989)
It was discovered that glutamate toxicity could be prevented to some extent by isolated or synthetic THC or CBD. (Hampson, Grimaldi, Axelrod, & Wink, 1998) The CBs were also tested in vitro on neuronal cultures exposed to glutamate. CBD and other CBs were examined as neuroprotectants in rat cortical neuron cultures exposed to toxic levels of the neurotransmitter, glutamate.
According to Hampson, et al., the psychotropic CB receptor agonist delta 9-THC and a non-psychoactive constituent of marijuana—CBD, both reduced the n-methyl-d-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, as well as kainate receptor mediated neurotoxicity. Neuroprotection was not affected by CB receptor antagonist, indicating a CB receptor-independent mechanism of action. (Hampson, et al., 2000)
Glutamate toxicity can be reduced by antioxidants. Using cyclic voltammetry and a fenton reaction-based system, it was demonstrated that CBD, THC and other CBs are potent antioxidants. As evidence that CBs can act as antioxidants in neuronal cultures, CBD was demonstrated to reduce hydroperoxide toxicity in neurons. In a head to head trial of the abilities of various antioxidants to prevent glutamate toxicity, CBD was superior to both alpha-tocopherol and ascorbate in protective capacity. The preliminary studies in a rat model of focal cerebral ischemia suggest that CBD may be at least as effective in vivo as seen in these in vitro studies. (Hampson, et al., 2000)
The example illustrated in FIG. 2, incorporated herein by reference, compares the oxidation potentials of CBs and the antioxidant Butylated Hydroxytoluene (BHT). Effect of CBD and THC on dihydrorhodamine oxidation. CBs were compared with BHT for their ability to prevent tert-butyl hydroperoxide-induced oxidation of dihydrorhodamine. This experiment was repeated four times with essentially the same results. (Hampson, Grimaldi, Axelrod, & Wink, 1998)
A study by Formukong, Evans, & Evans was undertaken to determine the analgesic and anti-inflammatory activity of various CBs and CB pre-cursors. Oral administration of CBD was found to be the most effective at inhibition of phenyl-p-benzoquinone-induced writhing in mice. THC and CBN were found to be least effective at reducing analgesia and inflammation. (Formukong, Evans, & Evans, 1988) Another study undertaken by Hampson, Grimaldi, Axelrod, & Wink, as exemplified in FIG. 1, incorporated herein by reference, compares the oxidation potentials of CBs and the antioxidant BHT. (Hampson, Grimaldi, Axelrod, & Wink, 1998)
Further, certain anecdotic evidence suggests that CB-containing plant extracts are demonstrating higher efficacy in treatment of some neurodegenerative diseases than essentially pure CBs. Specifically, CB-containing plant extracts comprising, as a predominant CB, THC and CBD—particularly effective in the retardation of neural degeneration.
Several pharmaceutical products exist which contain either phytocannabinoids (natural) or synthetic CBs. For example, dronabinol (Marinol) is the International Nonproprietary Name (INN) for an encapsulated THC product which has been used therapeutically as an appetite stimulant, antiemetic, and analgesic, either as an inhalant or as an oral drug. Also, nabilone (Cesamet) is a synthetic analog of dronabinol (Marinol), while Sativex is a CB extract oral spray containing THC, and other CBs that are used to treat neuropathic pain, spasticity, nausea associated with cancer chemotherapy, and stimulate appetite in HIV patients. Further, rimonabant (marketed under various tradenames) is a selective cannabinoid receptor antagonist used as an anti-obesity drug and as a smoking cessation. Several other cannabinoid-containing products exist.
Thus, considering the therapeutic effect of compounds containing CBs, especially (—)-Δ9-trans-THC, there is a continuing need for improving existing CB-containing products as well as a need for new products and delivery systems containing CBs, especially in the pharmaceutical field.
The use of cannabis as a medicine has long been known and during the 19th century preparations of cannabis were recommended as a hypnotic sedative which were useful for the treatment of hysteria, delirium, epilepsy, nervous insomnia, migraine, pain and dysmenorrhea. Until recently the administration of cannabis to a patient was mainly achieved by preparation of cannabis by decoction in ethanol, which could then be swallowed or by the patient inhaling the vapors of cannabis by smoking the dried plant material.
It is important to note that side effects, as well as therapeutic effects, vary depending on the CBs, concentration of CBs, or ratio of CBs in formulations. Smoking cannabis has been associated with lung cancer risk, although oral administration is also problematic due to deposition of CBs into fatty tissue, from which they are released slowly, causing variability in plasma concentrations. (Kluger, Triolo, Jones, & Jankovic, 2015) There is also an important risk of abuse with marijuana and cannabis-based drugs due to the psychotropic effect of THC. (Haberstick, et al., 2014) Studies of marijuana outside of the medical context estimate 9% of persons using cannabis may become addicted and experience symptoms of withdrawal after quitting the drug. (Warner, Kessler, Hughes, Anthony, & Nelson, 1995) These, along with legal issues, are some of the main difficulties today in treating patients with natural CBs. Inconsistent drug delivery systems (smoking, oral sprays, inhalers, and others), inconsistent compounds due to the natural variances of CBs, inherent instability of certain CBs, as well as abuse potential due to the psychotropic effect, are some of the areas that this invention aims to overcome by providing a standardized, medical-grade CB-based pharmaceutical and delivery system for effective treatment of movement disorders with minimal psychotropic effect and therefore abuse potential.
Recent methods have sought to find new ways to deliver CBs to a patient including those which bypass the stomach and the associated first pass effect of the liver which can remove up to 90% of the active ingested dose and avoid the patient having to inhale unhealthy tars and associated carcinogens into their lungs. Such dosage forms include administering the CBs to the sublingual or buccal mucosae, inhalation of a CB vapor by vaporization or nebulization, enemas or solid dosage forms such as gels, capsules, tablets, pastilles and lozenges.
To attain the required purity of isolated CBs, up to at least 95% by total weight, consistent ratio of CBs in the formulation, attain pharmaceutical-grade stability of active CBs, effective and consistent delivery system for treating multiple conditions, as well as therapeutically-effective treatment methods—requires a know-how that is proposed in this document. However, there is existing prior art, such as patents, published patent applications, academic work, and other, that is related but distinct from the proposed invention.
The U.S. Pat. No. 7,449,589, referenced herein, demonstrates one of many processes for purifying (-)-Δ9-trans-tetrahydrocannabinol and shows various cannabinoid compounds, including THC, CBD, and CBN. The THC reportedly has at least eight individual isomers of which (-)-Δ9-trans-tetrahydrocannabinol ((-)-Δ9-trans-THC) is the main and most active isomer. Although Δ8-tetrahydrocannabinol has similar activity as (-)-Δ9-trans-THC, it is only approximately 75% as potent and also tends to degrade to other compounds including CBN. (U.S. Pat. No. 7,449,589 B2, 2004)
The U.S. Pat. No. 8,628,796, referenced herein, discloses an encapsulated THC composition, including (-)-Δ9-trans-THC purportedly having improved stability. The disclosure emphasizes that the stability can be improved by including bases (e.g., amines) in the formulation. In addition, the stability of the compositions disclosed is best preserved by storing the compositions in a sealed container, such as in a capsule, and under refrigerated conditions. Specifically, the disclosure asserts that one embodiment of the invention described therein overcomes the deficiencies of prior art oral dosage forms containing (-)-Δ9-trans-THC by utilizing hard gelatin capsules, instead of soft gelatin capsules. As stated in the disclosure, unlike soft gelatin capsules, hard gelatin capsules do not contain glycerol—a major cause of instability for the active (-)-Δ9-trans-THC pharmaceutical ingredient. The disclosure purports to provide a stable product, such as one that does not degrade to an unacceptable extent during the desired shelf-life of the dosage form. (U.S. Pat. No. 8,628,796 B2, 2005)
The U.S. Pat. No. 7,968,594, referenced herein, discloses the invention that relates to treatment of cancer related pain and constipation. The subject in need is administered a combination of CBD and delta-9-THC in a predefined ratio by weight of approximately 1:1 of CBD to THC. (U.S. Pat. No. 7,968,594 B2, 2005)
The U.S. Pat. No. 9,205,063, also published as the U.S. Pat. No. 8,673,368, referenced herein, discloses in one aspect, a method that relates to use of one or more CB-containing plant extracts consisting essentially of an extract of Cannabis sativa obtained by supercritical or subcritical extraction with CO2; and where said extract is used in the prevention or treatment of neural degeneration, wherein the one or more CB-containing plant extracts comprise a CB-containing fraction, consisting essentially of the major CB, a minor CB, and one or more other CBs, and a non-CB containing fraction. (U.S. Pat. No. 9,205,063 B2, 2014) (U.S. Pat. No. 8,673,368 B2, 2007)
The U.S. Pat. Application No. 20,140,228,438, referenced herein, discloses the invention that relates to CBs for use in the prevention or treatment of neurodegenerative diseases or disorders. Preferably, the CBs are cannabichromene (CBC) cannabidivarin (CBDV) and/or cannabidivarin acid (CBDVA). More preferably, the neurodegenerative disease or disorder to be prevented or treated is Alzheimer's Disease. (US Patent No. US20140228438 A1, 2012)
The U.S. Pat. Application No. 20,060,135,599, referenced herein, discloses the invention that relates to the use of one or more CBs in the treatment of neuropathic or chronic pain. A method of treating brachial plexus avulsion in a human patient comprising administering to a patient in need thereof effective amount one or more CBs. (US Patent No. US20060135599 A1, 2003)
The U.S. Pat. No. 8,980,940, referenced herein, discloses a composition comprising a high purity CB, an acid, and a pharmaceutically-acceptable solvent that achieves room temperature stability for over 24 months. The acid improves the stability of the composition and the solvent enhances the solubility of the acid, thereby allowing the acid to have an improved stabilizing effect on the highly pure CB. Preferably, the solvent is an alcohol and, more preferably, the composition contains an oil. A method for making the composition includes combining the CB and the solvent and evaporating a portion of the solvent, along with adding an acid to the composition, before, during, or after the evaporating step. A method for making and storing the composition includes storing the composition in a manner adapted to maintain its stability. (U.S. Pat. No. 8,980,940 B2, 2011)
The U.S. Pat. Application No. 20,080,175,902, referenced herein, discloses methods for slowing the progression of MS comprising administering a therapeutically effective amount of CB to a patient suffering from MS. A method of slowing the progression of MS in a patient in need thereof, comprising administration of a pharmaceutical composition containing an effective amount of therapeutically effective CB on a regular basis; the administration occurring over a period of time: at least about 16 weeks, at least about 27 weeks, at least about 40 weeks and at least about 52 weeks. (US Patent No. US20080175902 A1, 2007)
The U.S. Pat. Application No. 20,060,167,084, referenced herein, discloses methods of, inter alia, treating and/or preventing symptoms associated with MS and its relapse. A method of treating and/or preventing symptoms associated with MS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising delta-9-THC. (US Patent No. US20060167084 A1, 2005)
The U.S. Pat. Application No. 20,040,018,151, referenced herein, discloses in one aspect, a method for promoting normal motor function in Amyotrophic Lateral Sclerosis (ALS) patients. The method comprises administering a compound that is an anandamide/CB receptor/acceptor agonist to a mammal having observable motor function, and evaluating one or more indicia of motor function in said mammal, wherein a compound that promotes normal motor function is identified. More preferably, the mammal to which the administration is made has one or more ALS or Motor Neuron Disease (MND) symptoms and such one or more symptoms include at least one of the observable motor functions being evaluated. (US Patent No. US20040018151 A1, 2003)